The central pathophysiologic event in sickle cell disease is the formation of an intraerythrocytic gel of deoxyhemoglobin S, resulting in intracellular and vascular rheological events which produce obstruction. The overall aim of this work is to elucidate the kinetics and mechanisms of assembly of hemoglobin S gels with the health related purposes of understanding the molecular mechanisms of pathogenesis in, and developing a specific therapy, not now existent, for sickle cell disease. The fundamental rationale for this approach is based on accumulating evidence that pathogenesis and its marked variability depend on the physical chemistry, and particularly the kinetics of gelation and its highly mutable nature. This mutability results from the existence of metastable states and highly cooperative phenomena. Gle assembly occurs in three experimentally defined stages: (a) nucleation (during which no significant rheological changes occur), (b) growth of long, rod-like fibers from nuclei and (c) alignment of these fibers to form liquid crystalline regions (tactoids), associated with separation into conugate anisotropic and isotropic phases. Most of the work planned will address pre-gelation aggregation, either of the kinetic kind, occurring during the first stage, or of the equilibrium kind, occurring at concentrations of hemoglobin S which are insufficient to induce gelation. Low angle elastic light scattering and quasi-elastic light scattering will be used for most studies, supplemented by electgron and polarizing microscopy and rheological measurements. The specific aims are to characterize the aggregates observed in respect to molecular weight, shape (as measured by radius of gyration, excluided volume non-ideality, and diffusion coefficient), sequence of development and alignment.